A Narrative Review of Microsporidial Infections of the Cornea.

Microsporidia are a rare and commonly misdiagnosed cause of corneal infection, accounting for approximately 0.4% of cases of microbial keratitis in some populations. Ocular microsporidiosis most often presents as either microsporidial keratoconjunctivitis (MKC) or microsporidial stromal keratitis (MSK). Though these two clinical entities exhibit similar symptomology, they are distinguished from one another by the time course for disease progression, findings on slit-lamp examination, and response to medical therapy. This review summarizes the current literature on the etiology and clinical presentation of microsporidial infections of the cornea and highlights ongoing developments in available diagnostic modalities and treatment regimens.

Topical Recombinant Human Nerve Growth Factor (Cenegermin) for Neurotrophic Keratopathy: A Multicenter Randomized Vehicle-Controlled Pivotal Trial.

PURPOSE: To evaluate the efficacy and safety of topical cenegermin (recombinant human nerve growth factor) in patients with neurotrophic keratopathy. DESIGN: Multicenter, randomized, double-masked, vehicle-controlled trial. PARTICIPANTS: Patients with neurotrophic persistent epithelial defect with or without stromal thinning. METHODS: The NGF0214 trial, conducted among 11 sites in the United States, randomized 48 patients 1:1 to cenegermin 20 µg/ml or vehicle eye drops, 6 drops daily for 8 weeks of masked treatment. Follow-up was 24 weeks. Safety was assessed in all patients who received study drug. Efficacy was assessed by intention to treat. MAIN OUTCOME MEASURES: The primary end point was healing of the neurotrophic lesion (persistent epithelial defect or corneal ulcer) after 8 weeks of masked treatment. Masked central readers measured neurotrophic lesions in randomized clinical pictures, then assessed healing status conventionally (<0.5 mm of fluorescein staining in the greatest dimension of the lesion area) and conservatively (0-mm lesion staining and no other residual staining). Secondary variables included corneal healing at 4 weeks of masked treatment (key secondary end point), overall changes in lesion size, rates of disease progression, and changes in visual acuity and corneal sensitivity from baseline to week 8. RESULTS: Conventional assessment of corneal healing showed statistically significant differences at week 8: compared to 7 of 24 vehicle-treated patients (29.2%), 16 of 23 cenegermin-treated patients (69.6%) achieved less than 0.5 mm of lesion staining (+40.4%; 95% confidence interval [CI], 14.2%-66.6%; P = 0.006). Conservative assessment of corneal healing also reached statistical significance at week 8: compared to 4 of 24 vehicle-treated patients (16.7%), 15 of 23 cenegermin-treated patients (65.2%) achieved 0 mm of lesion staining and no other residual staining (+48.6%; 95% CI, 24.0%-73.1%; P < 0.001). Moreover, the conservative measure of corneal healing showed statistical significance at week 4 (key secondary end point). Compared to vehicle, cenegermin-treated patients showed statistically significant reductions in lesion size and disease progression rates during masked treatment. Cenegermin was well tolerated; adverse effects were mostly local, mild, and transient. CONCLUSIONS: Cenegermin treatment showed higher rates of corneal healing than vehicle in neurotrophic keratopathy associated with nonhealing corneal defects.

Intraoperative Optical Coherence Tomography-Assisted Descemet Stripping Automated Endothelial Keratoplasty for Anterior Chamber Fibrous Ingrowth.

PURPOSE: Here, we present the first reported case of intraoperative optical coherence tomography (OCT)-assisted Descemet membrane stripping automated endothelial keratoplasty (DSAEK) in a patient with anterior segment fibrous ingrowth. METHODS: A 61-year-old woman with corneal edema and chronic angle-closure glaucoma secondary to fibrous ingrowth after 2 glaucoma shunt device implantations underwent dissection and removal of anterior chamber fibrous ingrowth and DSAEK. The surgical techniques using intraoperative OCT and outcome are described. RESULTS: Intraoperative OCT provided a clear dissection plane of the fibrous membranes in the anterior chamber and view of their relation to the iris and corneal endothelium, despite an opacified cornea. The placement of the donor lenticule and absence of interface fluid were also verified intraoperatively. The postoperative course was uncomplicated with satisfactory outcome. CONCLUSIONS: We conclude that intraoperative OCT is a useful tool during DSAEK surgery, particularly in complicated cases such as anterior segment fibrous ingrowth and significant corneal edema.

Optical Coherence Tomography Imaging of the Palisades of Vogt to Assist Clinical Evaluation and Surgical Planning in a Case of Limbal Stem-Cell Deficiency.

PURPOSE: To describe the use of volumetric optical coherence tomography (OCT) imaging to assist evaluation of a patient referred for autologous limbal stem-cell transplant. METHODS: This is a case report of a 50-year-old patient presenting with unilateral limbal stem-cell deficiency who was referred for autologous limbal stem-cell transplant. The presence of Salzmann nodules in the donor eye raised questions about the efficacy of transplantation, prompting examination of both eyes using volumetric OCT imaging to determine whether there were palisades of Vogt (POV) present. Image volumes were acquired in all clock hours and were compared against those of an age-matched normal subject. RESULTS: Palisades were found in both eyes, although in both eyes there were fewer palisade ridges, and those that were present were not as distinct as those of the normal subject. The OCT volumes also showed that stromal scarring was present only in the anterior stroma of the intended transplant eye. These findings suggested that the patient may be able to sustain a deep anterior lamellar keratoplasty without an autologous transplant, which would spare any insult to the opposing eye and require less surgery to restore vision in the affected eye. Nine months postsurgical follow-up revealed significant improvement in visual acuity and no scar tissue development. CONCLUSION: The OCT evaluation of the POV provides detailed information to the clinician that may assist in diagnosis and evaluation of patients before transplantation. Further development of this technique is necessary to make it clinically available.

Femtosecond laser-assisted decagonal deep anterior lamellar keratoplasty.

OBJECTIVE: To assess the use of a new polygonal trephination pattern for deep anterior lamellar keratoplasty (DALK) assisted by femtosecond laser. DESIGN: Prospective, nonrandomized clinical study. METHODS: Twenty-four eyes underwent decagonal DALK. All except 1 had advanced keratoconus. A laser was used to create decagonal cuts on both donor and recipient corneas. All patients were assessed for uncorrected visual acuity, best spectacle-corrected visual acuity (BCVA), and keratometry by Pentacam pre- and postoperatively. RESULTS: All eyes were treated successfully without intraoperative complications. All patients were followed for 18 months. Mean ± SD of postoperative BCVA was 0.26 ± 0.16 (logarithm of minimal angle of resolution), and there was a significant improvement in BCVA after 6 months. At 18 months, mean ± SD postoperative average K was 44.48 ± 0.87 D, which was significantly lower than preoperative average K (58.42 ± 12.1). Postoperative astigmatism at 18 months (mean ± SD: 1.82 ± 0.67) was significantly lower than that at 6 months (mean ± SD: 3.27 ± 0.81) (p = 0.001). CONCLUSIONS: Use of the decagonal trephination profile was effective to perform DALK. This study showed promising visual and refractive results. Longer follow-up, larger pool of patients, and comparative studies are necessary to determine advantages and optimal surgical settings of this technique.

Diagnosis and management of opacified silicone intraocular lenses in patients with asteroid hyalosis.

UNLABELLED: We analyzed 3 calcified silicone IOLs from 2 patients with a history of asteroid hyalosis. In both cases, posterior capsule opacification had been diagnosed and a laser capsulotomy performed before referral. Subsequently, both IOLs were exchanged with hydrophobic acrylic IOLs that were placed in the sulcus. The IOL exchange was challenging due to the open capsule. Light microscopy demonstrated that the white deposits on the explanted IOLs formed an almost confluent crust in some areas, interspersed with clear areas on the posterior optic surfaces. The findings in our cases and in other reported cases may affect the choice of IOL in the presence of asteroid hyalosis. Also, ophthalmologists may consider deferring laser posterior capsulotomy treatment in a calcified silicone IOL to facilitate an IOL exchange procedure. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Does mitomycin C cause toxicity in the cornea after photorefractive keratectomy? A comparative wound-healing study in a refractive surgery animal model.

PURPOSE: In this study, we investigated the wound-healing process after photorefractive keratectomy with mitomycin C (MMC) in hen corneas. In addition, we evaluated the synergistic effect of ethanol and MMC. METHODS: Forty-eight adult hens were divided into 3 groups: A: ethanol-assisted debridement plus MMC; B: mechanical debridement plus MMC; and C: mechanical debridement (MMC-untreated control). Photorefractive keratectomy was performed, and the animals were followed up for up to 60 days. Epithelial healing was measured with fluorescein. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end-labeling assay and proliferation was measured by BrdU incorporation. Both myofibroblast differentiation and collagen deposition were evaluated by immunofluorescence and histology. RESULTS: Epithelial wound closure was similar in all 3 groups (P > 0.05). Significant reduction in haze was observed in groups A and B compared with C (P < 0.01), but there was no difference between groups A and B (P > 0.05). Furthermore, there was no difference in the number of apoptotic cells between groups. Proliferation was delayed in both groups A and B compared with C (P < 0.01), but groups A and B did not differ significantly (P > 0.05). Myofibroblasts, cellular density, and collagen deposition were lower in both groups A and B compared with C (P < 0.01), but they were not significantly different from each other (P > 0.05). CONCLUSIONS: Topical application of MMC in hen corneas reproduces the wound healing observed in humans by reducing haze, keratocyte proliferation, myofibroblast differentiation, and new collagen deposition. Synergistic cytotoxic effects of ethanol and MMC were not observed.

Application of adipose-derived stem cells on scleral contact lens carrier in an animal model of severe acute alkaline burn.

PURPOSE: To evaluate the therapeutic effect of human adipose-derived stem cells (hASCs) overlaid on a scleral contact lens (SCL) carrier in a rabbit model of ocular alkaline burn. MATERIALS AND METHODS: After inducing alkaline burn in 11 New Zealand white rabbits, hASCs cultured on SCLs were placed on the right eye of 5 rabbits, SCLs without cells were used in 5, and no treatment was applied in 1 eye. Each eye was examined and photographed for corneal vascularization, opacities, and epithelial defect in week 1, 2, and 4 after surgery. After 1 month, rabbits were killed and the corneas were removed and cut in half for electron and light microscopy examination. RESULTS: Human adipose-derived stem cells were attached to SCL surface and confluent easily. Human adipose-derived stem cells on SCL eyes showed smaller epithelial defect, less corneal opacity, corneal neovascularization relative to SCL eyes. Both groups showed no symblepharon. However, the cornea in the untreated eye was melted in 2 weeks and developed severe symblepharon. CONCLUSION: Human adipose-derived stem cells on SCL can reduce inflammation and corneal haziness in severe ocular alkaline burn injury in rabbits.

First report of keratitis in familial cold autoinflammatory syndrome.

OBJECTIVE: To report corneal manifestations of familial cold autoinflammatory syndrome (FCAS) for the first time. DESIGN: small case series PARTICIPANTS: Medical records of three members of a single family were reviewed after obtaining institutional review board (IRB) approval and informed consent. METHODS: All three members presented with a long history of maculopapular rash after cold exposure starting in childhood associated with nausea, low-grade fever, fatigue and arthralgia that lasted less than 24 hours. Their ocular manifestations consisted of ocular pain, photophobia and keratitis with subsequent stromal haziness. RESULTS: Patients underwent systemic therapy with canalinumab (Ilaris). They responded very well to repeated injections of Ilaris without side effects. CONCLUSIONS: FCAS causes lifelong debilitating effects that restrict patients' daily activities. Ilaris is an FDA-approved treatment for this condition and that typically results in dramatic improvement in clinical and laboratory measures of inflammation, and is well tolerated. Our report is the first small case series of FCAS with keratitis that responded to Ilaris beautifully.

Surgical management for postkeratoplasty glaucoma: a meta-analysis.

PURPOSE: To perform a meta-analysis on postkeratoplasty glaucoma and directly compare the affect of trabeculectomy, cyclophotocoagulation (CPC), and glaucoma drainage device (GDD) on intraocular pressure (IOP) control and corneal graft survival. METHODS: We searched Medline (Ovid, PubMed), EMBASE, and The Cochrane Library databases for clinical articles that maintained our inclusion criteria. The primary outcome measures were IOP control and overall corneal graft survival. The secondary outcomes were failure rate of the primary glaucoma procedure and change in visual acuity. We used 1-way analysis of variance weighed by the number of participants in each study to compare the outcomes. RESULTS: Information from a total of 266 eyes was collected from 13 articles. Trabeculectomy reduced IOP by 13.6 mm Hg compared with 20.4 mm Hg with CPC and 20.2 mm Hg with GDD (P<0.001). The failure rate of glaucoma surgery was highest after trabeculectomy 37% (95% CI, 31.4%-41.9%) compared with 20.7% (95% CI, 17.6%-23.7%) after CPC and 16% (95% CI, 13.8%-18.9%) after GDD and this was statistically significant (P<0.001). GDD was associated with higher rate of corneal graft failure (35%) than either CPC or trabeculectomy (21% and 24%, P=0.001 and P<0.001, respectively). The percentage of patients who experienced worsening of vision was the highest after CPC (26%) and the least with GDD (20%). CONCLUSIONS: Our meta-analysis shows that in patients with postkeratoplasty glaucoma, GDD is associated with greater IOP control, the lowest glaucoma surgery failure rate, and less vision loss compared with other forms of glaucoma surgery. However, GDD surgery is also associated with higher rate of graft failure.

Lamellar keratoplasty: a literature review.

The concept of lamellar keratoplasty (LK) is not new. However, newer forms of lamellar keratoplasty techniques have emerged in the last decade or so revolving around the concept of targeted replacement of diseased corneal layers. These include anterior lamellar keratoplasty (ALK) techniques that aim to selectively replace diseased corneal stroma and endothelial keratoplasty techniques aiming to replaced damaged endothelium in endothelial disorders. Recent improvements in surgical instruments and introduction of new techniques as well as inherent advantages such as preservation of globe integrity and decreased graft rejection have resulted in the reintroduction of LK as an acceptable alternative to conventional PK. In this review, indications, benefits, limitations, and outcomes of various anterior and posterior lamellar keratoplasty techniques are discussed.

Differentiation of Human Adipose-derived Stem Cells along the Keratocyte Lineage In vitro.

PURPOSE: To evaluate differentiation of human adipose-derived stem cells (hASCs) to the keratocyte lineage by co-culture with primary keratocytes in vitro. MATERIALS AND METHODS: A co-culture system using transwell inserts to grow hASCs on bottom and keratocytes on top in keratocyte differentiating medium (KDM) was developed. hASCs that were cultured in complete culture medium (CCM) and KDM were used as control. After 16 days, hASCs were examined for morphologic changes and proliferation by cell count. qRT-PCR and flow cytometry were used to detect the expression of aldehyde dehydrogenase 3 family, member A1 (ALDH3A1) and keratocan. RESULTS: hASCs became more dendritic and elongated in co-culture system relative to CCM and KDM. The doubling time of the cells was longer as differentiation progressed. qRT-PCR showed a definite trend towards increased expression of both ALDH3A1 and keratocan in co-culture system despite statistically non-significant p-values. Flow cytometry showed significantly increased protein levels of ALDH3A1 and keratocan in co-culture system relative to CCM group (p < 0.001) and even relative to KDM group (p < 0.001 for ALDH3A1 and p < 0.01 for keratocan). CONCLUSION: The co-culture method is a promising approach to induce differentiation of stem cell populations prior to in vivo applications. This study reveals an important potential for bioengineering of corneal tissue using autologous multi-potential stem cells.

Adipose-derived stem cells on hyaluronic acid-derived scaffold: a new horizon in bioengineered cornea.

OBJECTIVE: To evaluate the ability of human adipose-derived stem cells (h-ASCs) to survive and differentiate in corneal stroma. METHODS: Our experiment consisted of 2 phases. First, we cultured h-ASCs in different types of hyaluronic acid (HA)-derived synthetic extracellular matrixes (sECMs) to determine the capability of proliferation and survival of the cells in hydrogels. Second, h-ASCs were grown in plastic flasks, labeled with an intracytoplasmic membrane fluorescent molecule, transferred onto different types of sECMs or the native HA product, and then inserted into the corneal stroma of the rabbits. After 10 weeks, we assessed the viability of the stem cells and the expression of cornea-specific proteins. RESULTS: The in vitro study showed that the HyStem-HP hydrogel had the highest yield of cells (1.1 × 10(6)/mL) compared with other types of HA-derived sECMs culture media, and the cells grown in the HyStem-HP hydrogel appeared more elongated and fibroblastlike. The in vivo study demonstrated that the labeled h-ASCs could be identified in the stroma with any type of sECM. The HA-derived sECMs, particularly the HyStem-HP hydrogel, showed better survival and cell morphologic features compared with pure HA. Immunostaining of keratocan, aldehyde dehydrogenase, and type I collagen revealed that the stem cells had expressed human cornea-specific proteins. CONCLUSION: Human adipose-derived stem cells can be successfully grown on HA-derived sECMs in vivo and can express human cornea-specific proteins. CLINICAL RELEVANCE: Human ASCs on an HA-derived scaffold may be used as a source of keratocytes to regenerate extracellular matrix-like material in situations where the cornea stroma has been compromised.

Descemet stripping automated endothelial keratoplasty using donor corneas with previous laser in situ keratomileusis or photorefractive keratectomy: a case series and donor cap histopathology.

PURPOSE: To report outcomes in Descemet stripping automated endothelial keratoplasty (DSAEK) using donor tissue from eyes that have had previous refractive surgery and to report histopathology of the donor free cap. METHODS: Retrospective case series. Preoperative and postoperative data were collected on each patient, and donor information was collected. Histopathologic evaluation was carried out on donor caps to determine the stability of the laser in situ keratomileusis (LASIK) flap and smoothness of the microkeratome cut during preparation of the donor. RESULTS: DSAEK was performed on 7 eyes using donors that had undergone photorefractive keratectomy (PRK) or LASIK. One patient received PRK donor tissue, had no interface haze, and had improvement in vision. All but one patient who received LASIK donor tissue had improvement in vision, and that patient had severe graft folds noted intraoperatively that persisted. Histopathologic examination of 3 donor caps showed mild to moderate dehiscence of the LASIK flap, but the cut interface was consistent with normal donor tissue preparation histopathology. CONCLUSIONS: We report the first case of DSAEK using PRK donor tissue, which was successful. Our experience with LASIK donor tissue was comparable to nonrefractive donor tissue with the exception of the persistent donor macrofolds in one patient.